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Authors

Antonio Curti; Alessandro Rambaldi; Chiara Cattaneo; Roberto Cairoli; Matteo Della Porta; Patrizia Chiusolo; Federico Lussana; Marta Ubezio; Valentina Mancini; Isabel Cano; Carmen Besliu; Christian Hove Claussen; Rosalinda Gatto; Patrizia Crivori; Elena Colajori; Alessio Somaschini; Cristina Davite; Antonella Isacchi; Elena Ardini; Lisa Mahnke; Pau Montesinos

Title

Abstract CT025: NMS-03592088, a novel, potent FLT3, KIT and CSF1R inhibitor with activity in FLT3 positive acute myeloid leukemia patients with prior FLT3 inhibitor experience

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	83	8_Supplement	April 15, 2023

URL

https://aacrjournals.org/cancerres/article/83/8_Supplement/CT025/725421/Abstract-CT025-NMS-03592088-a-novel-potent-FLT3

Abstract Text

Background: FLT3 mutations occur in approximately 30% of AML patients and are associated with aggressive disease. Despite the approval of midostaurin and gilteritinib, the prognosis for FLT3+ patients with relapsed or refractory disease is poor. NMS-088 is a novel, potent FLT3, KIT and CSF1R inhibitor with superior preclinical activity compared with approved FLT3 inhibitors in different FLT3-driven models. In addition, NMS-088 is active on FLT3 resistance mutation F691L. Dose escalation results from a Phase I/II study to establish safety, dose selection and preliminary clinical activity for NMS-088 in patients with R/R AML and CMML are described. Methods: In the Phase I 3+3 escalations, NMS-088 is administered daily for 21 of 28 days (schedule A) or continuously (schedule B). Patients must have R/R AML or CMML unsuitable for standard therapy. The primary objective is the MTD or MAD as assessed by DLTs. Secondary endpoints include safety, PK and ELN response. Results: as of January 26, 44 R/R AML or CMML patients were treated at doses from 20 to 360 mg/day in A or from 120 to 250 mg/day in B. Median age was 64 yrs, 41 pts had AML and 3 pts had CMML, median number of prior lines was 2 (range 1 to 10). FLT3 mutations were present in 24 out of 41 AML pts (20 FLT3-ITD, 2 FLT3 D835 and 2 FLT3-ITD and D835). The majority of pts with FLT3+ AML had received prior FLT3 inhibitors (86.4%). NMS-088 showed manageable safety with no MTD characterized. One pt had DLT (abnormal posture, decreased activity, dyspnea G3 and eyelid ptosis G1) at 360 mg in A (at day 21) and one pt had DLT (eyelid ptosis G3) at 180 mg in B (at day 29), both suggestive for myasthenic syndrome. Three additional pts experienced possible myasthenic syndrome at doses ≥ 180 mg. Overall the most frequent treatment emergent related adverse events (≥10%) were nausea (any grade 20.5%), vomiting (13.6%), asthenia (11.4%). Discontinuations due to related AEs were as follows: 2 DLT pts per protocol, 2 pts due to nausea (G1; day 161 at 270 mg) and myasthenia gravis (G3; day 39 at 300 mg in a pt with baseline AChR antibodies). There was a dose-dependent trend for response. A total of 5 out of 12 evaluable pts with FLT3+ AML treated at dose ≥ 300 mg achieved a response with 2 CRi, 1 CRi/MLFS and 2 MLFS. Remarkably, all these pts had received prior midostaurin and 2 pts received both midostaurin and gilteritinib. Two pts with response withdrew from treatment to receive HSCT (DoR 1.0+ mos each). For other responding pts DoR was 1.3, 2.8 and 7.9 mos. Conclusions: NMS-088 showed clinical efficacy in pts with FLT3+ R/R AML, including pts who have failed prior FLT3 inhibitors. Together with the manageable safety observed, these results warrant further development of this drug including potential as a novel valuable therapeutic option for pts who have exhausted available treatments. The trial is currently opened for enrollment (NTC03922100).

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
NMS-P088	NMS-P088	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
NMS-P088		NMS 03592088\|NMS-03592088\|NMS03592088\|NMS P088\|NMSP088	CSF1R Inhibitor 28 FLT3 Inhibitor 66 KIT Inhibitor 57	NMS-P088 inhibits FLT3, KIT, and CSF1R with activity against FLT3 F691L, potentially leading to antitumor activity (Cancer Res (2023) 83 (8_Supplement): CT025).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 act mut	acute myeloid leukemia	predicted - sensitive	NMS-P088	Phase I	Actionable	In a Phase I trial, NMS-P088 demonstrated manageable safety and preliminary efficacy with responses in 5 of 12 patients with acute myeloid leukemia harboring FLT3 mutations (Cancer Res (2023) 83 (8_Supplement): CT025; NCT03922100).	detail...